Successive crystal structure snapshots suggest the basis for MHC class I peptide loading and editing by tapasin.

Hafstrand I, Sayitoglu EC, Apavaloaei A, Josey BJ, Sun R, Han X, Pellegrino S, Ozkazanc D, Potens R, Janssen L, Nilvebrant J, Nygren PÅ, Sandalova T, Springer S, Georgoudaki AM, Duru AD, Achour A

Proc. Natl. Acad. Sci. U.S.A. 116 (11) 5055-5060 [2019-03-12; online 2019-02-26]

MHC-I epitope presentation to CD8+ T cells is directly dependent on peptide loading and selection during antigen processing. However, the exact molecular bases underlying peptide selection and binding by MHC-I remain largely unknown. Within the peptide-loading complex, the peptide editor tapasin is key to the selection of MHC-I-bound peptides. Here, we have determined an ensemble of crystal structures of MHC-I in complex with the peptide exchange-associated dipeptide GL, as well as the tapasin-associated scoop loop, alone or in combination with candidate epitopes. These results combined with mutation analyses allow us to propose a molecular model underlying MHC-I peptide selection by tapasin. The N termini of bound peptides most probably bind first in the N-terminal and middle region of the MHC-I peptide binding cleft, upon which the peptide C termini are tested for their capacity to dislodge the tapasin scoop loop from the F pocket of the MHC-I cleft. Our results also indicate important differences in peptide selection between different MHC-I alleles.

PubMed 30808808

DOI 10.1073/pnas.1807656116

Crossref 10.1073/pnas.1807656116

pmc: PMC6421438
pii: 1807656116
PDB: 6GB7
PDB: 6GB5
PDB: 6GB6